Generating a Systemic Immune Response Using Localized Delivery of Chemotherapy in Brain Tumors

胶质母细胞瘤(GBM)是成人最常见的原发恶性脑肿瘤，与 预后很差。免疫疗法已显示出在其他疾病中产生持久抗肿瘤活性的潜力 癌症的类型。特别是，选择性靶向检查点分子的药物，如抗CTLA-4和 抗PD-1抗体通过直接对抗肿瘤的 免疫逃避机制。这些药物的显著效果已经在晚期报道 黑色素瘤、肾细胞癌和肺癌的试验正在进行中。化疗，也就是 GBM患者护理标准的一部分，与免疫抑制效应和 有清髓剂的结果。我们实验室最近的数据显示，局部化疗可能是一种更好的治疗方法 替代全身化疗，因为它避免了这些不良影响。这样做的主要目标是 建议是了解GBM逃避免疫系统的主要机制以及如何阻止 这些机制配合局部化疗和检查点阻断，可有效增强免疫力 对GBM的回应。我们的数据表明，局部化疗联合抗PD-1 在原位胶质瘤模型中提高存活率和提供记忆T细胞的增加和保护 对抗肿瘤的再挑战。我们建议研究：1.基底膜患者潜在的反应生物标志物 作为我们机构正在进行的临床试验的一部分，接受LC和抗PD-1治疗。2.新抗原 LC在对化疗敏感和耐药的小鼠脑胶质瘤中产生的轮廓，以确定 对TCR多样性和抗肿瘤免疫反应的影响。3.负责以下工作的APC的位置和身份 LC诱导的抗原提呈。这些数据将与研究结果有直接的临床相关性，并可能 转化为临床试验和病人护理。我们预计从这些研究中产生的数据将 为化疗的一个以前未探索的方面提供新的见解，并作为 优化治疗效果和宿主免疫功能。从这个过程中获得的知识 这项研究无疑将为目前不成功的患者带来更好的治疗选择 使用GBM。

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is associated with a dismal prognosis. Immunotherapy has demonstrated potential to generate durable antitumor activity in other types of cancer. In particular, agents that selectively target checkpoint molecules, such as anti-CTLA-4 and anti-PD-1 antibodies, have accelerated the field of cancer immunotherapy by directly combating the tumor's mechanisms of immune evasion. Notable results with these agents have already been reported in advanced melanoma, renal cell carcinoma, and lung cancer and trials are underway in GBM. Chemotherapy, which is part of the standard of care for patients with GBM, has been associated with immunosuppressive effects and with myeloablative results. Recent data from our laboratory shows that local chemotherapy may be a better alternative to systemic chemotherapy given that it avoids these untoward effects. The main goal of this proposal is to understand the main mechanisms by which GBM evades the immune system and how to thwart these mechanisms with local chemotherapy and checkpoint blockade to enhance an effective immune response against GBM. Our data demonstrates that local chemotherapy in combination with anti-PD-1 increases survival and provides an increase in memory T cells in an orthotopic glioma model and protects against tumor re-challenge. We propose to study: 1. Potential biomarkers of response in patients with GBM treated with LC and anti-PD-1 therapy as part of an ongoing clinical trial at our institution. 2. The neoantigen profile generated by LC in intracranial chemosensitive and chemoresistant murine gliomas, to determine the impact on TCR diversity and anti-tumor immune response. 3. The location and identity of APCs responsible for antigen presentation induced by LC. These data will have direct clinical relevance for the findings and can be translational into clinical trials and patient care. We expect that the data generated from these studies will provide novel insights into a previously unexplored aspect of chemotherapy and serve as a foundation for optimizing the efficacy of therapy and host immune function against GBM. The knowledge obtained from this study will undoubtedly result in better therapeutic alternatives for current unsuccessful treatment for patients with GBM.